December 2022

The next chapter in Nitrosamine Testing

From recent experience we have seen a significant increase in requests related to API related nitrosamines. Based on industry feedback following the recent requirements regarding risk assessments of marketed products, a significant amount of small molecule related APIs, possibly 30%+, have been shown to have the potential to form active related nitrosamines.

Although we cannot share details of the actual levels of API related nitrosamines detected in sponsor samples due to confidentiality reasons there have certainly been cases where significant (>100µg/g) levels of API related nitrosamines have experimentally been found to be present.

As well as developing and validating methodology for API-related nitrosamines, our labs have supported a variety of root cause investigations which have included studies concerning in-situ formation of API related nitrosamines and the impact of addition of precursors, quench reagents etc.

The FDA and other major regulators (EMA, Health Canada, Anvisa etc.) have provided regular updates concerning results relating to API related nitrosamines from the industry. The following is taken from the FDA website:

‘Recently, FDA has received additional reports of certain types of nitrosamine impurities that formed in several drug products. These nitrosamine drug substance-related impurities (NDSRIs) are a class of nitrosamines sharing structural similarity to the API. NDSRIs can be generated during manufacturing or during the shelf-life storage period of the drug product. In some cases, the root cause of NDSRI formation has been attributed to nitrite impurities present in excipients at parts-per-million amounts. Nitrite impurities have been observed in a range of commonly used excipients (as well as water) and may lead to the formation of NDSRIs in certain drug products.’

FDA state that levels of NDSRIs should be controlled to ‘acceptable levels’ but have shown some flexibility in defining what these levels are e.g., Varenicline:

5/5/2022: UPDATE - FDA updates regulatory flexibility concerning N-nitroso-varenicline intake limits 

Update [5/5/2022] FDA is now confident in manufacturers’ ability to supply patients with varenicline containing the N-nitroso-varenicline impurity at or below the agency’s acceptable intake limit of 37 ng per day. Any newly manufactured varenicline for the U.S. market should have levels of the N-nitroso-varenicline impurity at or below that limit.

In July 2021, FDA announced it would not object to certain manufacturers distributing varenicline tablets containing N-nitroso-varenicline above FDA’s acceptable intake limit, but below the interim acceptable intake limit of 185 ng per day, until the impurity could be eliminated or reduced to acceptable levels. The agency’s current assessment shows manufacturers can adequately supply the market with varenicline at or below the acceptable intake limit of 37 ng per day.